Professor & Chairman, Department of Pharmacology
Director, Upstate Cancer Research Institute
State University of New York (SUNY)
Upstate Medical University
Syracuse, New York

Translating Basic Research to New Medicine:
Integration of Pharmacology, Biology, and Medicine in Transdisciplinary Basic and Translational Research
Biology of Disease
Genetics and Genomics
Protein
Structures
Human Genome
Computer-aided
Drug Design
Microarray
(HTP Sciences)
Pharmacology
Chemistry
Nanotechnology
New Medicine
Protein
Targeted
Drugs

Published in 2007
20 chapters by 70 leading experts and researchers from 25 universities,
Institutes, and companies around the world in the fields of pharmacology, pharmaceutical chemistry, drug design, cancer biology, neuroscience, and translational medicine (Dennis Carson, UCSD;
John Reed, Burnham; Paul Wender, Stanford;
Andrew Hamilton, Yale; Joseph Sodroski,
Harvard; Irwin Kuntz, UCSF, etc.)

Translational Research in Pharmacology:
Connecting Basic Science with Clinical Medicine
Cancer
Apoptosis: Bcl-2, Caspases, XIAP
Angiogenesis: Eph-Ephrin
Metastasis: Chemokine receptors
Immune & Infectious Diseases
Immune Response: CD4, CD8, IgSF
HIV infection: Chemokine receptors
HCV-WNV-Dengue
Pharmacolog y
Cell Signaling
Receptor-Ligand
Neurodegeneration
Dementia: Chemokine receptors
CNS injury repairs: Stem cell migration
Cardiovascular Diseases
Stem cell-based regeneration
APJ-Apelin; Wnt signaling
Translational Medicine
New Therapies

1.Cancer Apoptosis – Small molecule drugs targeting
Bcl-2 and IAP (cancer and neurodegenerative diseases
2.Cancer Metastasis – Small molecule and protein drugs targeting chemokine receptors (cancer, HIV, regenerative medicine for stroke, cardiac or brain injury)
3.Cancer Angiogenesis – Small molecule drugs targeting Eph receptors: cancer (breast cancer)

Over 10 years of research on a novel Bcl-2 inhibitor
HA14-1

Protein-protein Interactions in Programmed Cell Death
CrmA
FADD
Procaspase-8
Caspase-8
Bid tBid
Bcl-2
Bcl-x
L
The Bcl-2 Family
Bax
Bad
Mitochondria
Apaf-1
Procaspase-9 Cytochrome c
Caspase-9
Apoptosome XIAP
Survivin
The IAP Family
Smac/DIABLO
Caspase-3
Apoptosis
Huang, Chem. & Biol., 2002

Our Discovery of the First Reported Bcl-2 Inhibitor,
HA14-1, by Structure-based Computer Screening
Br
O
O
O
N
O
O
NH
2
PNAS, 2000

FPA Method to Measure Binding of HA14-1 to
Bcl-2 protein in vitro
100
50
Br
O
O
O
N
O
O
NH
2
IC
50
= 9 m
M
0
10 -6 10 -5
HA14-1 (M)
10 -4
Cancer Res., 2000
PNAS, 2000

HA14-1 has a significant killing of primary AML
100
75
50
25
0
AML
DMSO
AML
25 m
M
AML
50 m
M
M. Andreeff and co-workers, M. D. Anderson Cancer Center Blood, 2002

Potential clinical application:
HA14-1 (5 uM) sensitizes HL-60/Bcl-2 cells to γ radiation (very low dose)
120
100
80
60
40
20
0
0
0 m
M HA14-1
5.0 m
M HA14-1
24 h after cotreatment with HA14-1 and
γ radiation
0.2
0.4
Radiation (Gy)
0.6
Prof. Jing An; Oncogene, 2007

71 Studies/Publications by Many Other Laboratories on the
Application of HA14-1 for Various Cancers and
Other Dieseases (6/20/2008)
Glazova MV. et al., “Effects of selective Bcl-2 inhibitor
HA14-1 treatments on functional activity of magnocellular vasopressinergic neurons of rat hypothalamus”. Neurosci Lett. 2008 May 23;437(1):59-64.
Xing C. et al., “ sHA 14-1 , a stable and ROS-free antagonist against anti-apoptotic Bcl-2 proteins, bypasses drug resistances and synergizes cancer therapies in human leukemia cell”. Cancer Lett. 2008 Feb
8;259(2):198-208.
Pelkonen J. et al., “Brefeldin A triggers apoptosis associated with mitochondrial breach and enhances
HA14-1 - and anti-Fas-mediated cell killing in follicular lymphoma cells”. Leuk Res. 2007 Dec;31(12):1687-
700.
Nicol AJ. et al., “Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction”.
Br J Cancer. 2007 Feb 26;96(4):600-8.
Kessel D, Reiners JJ Jr. “Initiation of apoptosis and autophagy by the Bcl-2 antagonist HA14-1
”. Cancer
Lett. 2007 May 8;249(2):294-9.
Juin P. et al., “The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death”. Cancer Res. 2006 Mar 1;66(5):2757-64.
Pelkonen J. et al., “Multiparametric analysis of
HA14-1 -induced apoptosis in follicular lymphoma cells”.
Leuk Res. 2006 Sep;30(9):1187-92.

Chemokines And Receptors Are Involved In
Many Human Diseases
A dapted from A.E. Proudfoot, Nature | Immunology, 2:106-115, 2002

Mapping the locations of residues functionally important for
SMM-chemokines, HIV-1 or SDF-1 a on CXCR4 TM and ECL2 domains: Functional sites for SMM-chemokines and HIV-1 are distinct from those for SDF-1 a
The locations of the TM residues required for SDF-1 a binding are shown as white spots while those that are involved in HIV-1 coreceptor activity are shown as black spots.
ECL3
ECL2
N-terminus
TM6
TM7
ECL1
TM1
TM2 TM3
TM5
TM4
Tian et al., J. Virology , 2005
Choi et al. J. Virology , 2005

A more complete picture of CXCR4-ligand interaction based on crystal structure determination of the ligand and molecular modeling and mutational study of the receptor
SDF-1 a
NH
2
D20
E268
Y190
NH
2
Y21
Liu et al., J. Virology , 2007

Discovery of RCP168, a Novel CXCR4 Antagonist
C-terminal
RCP168
N-terminal vMIP-II
X-ray crystal structure of RCP168 vs. native vMIP-II determined by Prof. Ziwei Huang’s laboratory

Binding Affinity and Selectivity of SMM-Chemokines for
CXCR4, CCR5 and CCR2

Our SMM-Chemokine, RCP168 Compared With T20 Peptide,
The Recently Approved Drug Targeting
Viral gp41 Protein Mediated HIV-1 Entry
3-12-03
100
T20(HX/X4)
D10(HX/X4)
80
60
40
20
0
-500 0 500 1000 1500 2000 2500 3000 3500
Data from Prof. Joseph Sodroski, Harvard Medical School

Discovery of CXCR4 agonists to promote stem cell migration to the injury sites for regenerative repairs of injuries in the brain and heart in collaboration with Evan Snyder, Stuart Lipton
(neurodegeneration), Mark Mercola (cardiovascular disease)

Two Distinct Functional (Binding Vs. Signaling) Pockets on
CXCR4 Important for Antagonists and Agonists, Respectively
J. Virology, 2005, 2007

Our finding of distinctive binding and signaling pockets on
CXCR4

1. Two representative examples of pharmacologic discovery and characterization of novel small molecules and engineered peptides as basic research tools and leads for chemical and biologic drugs
2. Similar strategies for pharmaceutical research targeting cancer, infectious diseases, and neurodegeneration


Established in 2009; 60,000 s.f. space and 25 new faculty positions for future growth

Currently > 120 PIs/faculty members from basic science and clinical departments of Upstate and other universities (Downstate, Albany, Buffalo,
SU, Cornell, SUNY ESF)

Five programs in: (1) cancer biology; (2) viral oncology; (3) structural/chemical biology & bioinformatics; (4) stem cell research; and (5) drug discovery & translational research

Upstate Cancer Research Institute
Ziwei Huang, Director
Administration
Office
Internal Steering Committee
External Advisory Board
Cancer Research Programs
5 basic & clinical science programs
Each program headed program leader(s)
Upstate Cancer
Other
University’s
Core Facilities
Core Facilities
Drug Development Center
Education
Pre-doctoral (Ph.D. & M.D.) & postdoctoral training in cancer
Center

Andrew Hamilton, Ph.D.
, Vice Chancellor, University of Oxford
Dennis Carson, M.D.
, Director of UCSD Cancer Center
Curt Civin, M.D.
, Director of Center for Stem Cell Biology and
Regenerative Medicine, University of Maryland
Joseph Bertino, M.D.
, Associate Director and Chief Scientific
Officer of the Cancer Institute of New Jersey
Said Sebti, Ph.D.
, Moffitt Cancer Center
Wayne Hendrickson, Ph.D.
, Columbia University and HHMI
Paul Wender, Ph.D.
, Stanford University

Oxford’s Vice
Chancellor and scientific advisor
Andrew Hamilton
& business advisor
Philip Schein at the advisory visit in January, 2011

Grant funding
Investment
Donation
New faculty and students
Patients
Upstate Hospital
New cures and diagnostics
Biotech Center
New IPs, drugs and technologies

Attracting outstanding faculty from other renowned NCI designated cancer institutes/centers, bringing in multi million dollars in NIH grants
More than 7 new faculty in 2010, 3 from Pharmacology
1. Debashis Ghosh, Ph.D., Professor (Roswell Park Cancer
Institute) – cancer structural biology and drug discovery
2. Jing An, M.D., Ph.D., Associate Professor (Cancer Center of the Burnham Institute, La Jolla) – cancer drug screening and cancer and stem cell biology
3. Juntao Luo, Ph.D., Assistant Professor (UC Davis Cancer
Center) – cancer drug delivery and nanomedicine

1. One of 14 cancer institutes/centers (such as UCSD and UCSF cancer centers) in the country to receive
ACS IRG in 2010
2. Among a selected group of cancer institutes/centers in New York (such as Sloan Kettering and Roswell
Park) that have or had ACS IRG

MARION S. DOOLEY
1919-1945
ALLAN D. BASS
1945-1953
ALFRED FARAH
1953-1968
IRWIN WEINER
1969-1988
JOSE JALIFE
1989-2008
ZIWEI HUANG
2009-


6 core laboratories headed by pharmacology faculty, ~ 15,000 S.F.

80 faculty members in the Center
Target
Discovery
Bioassay
Screening
Structure
Determination
Drug
Discovery
Drug
Delivery
Preclinical
Development
Prof. Ziwei Huang
Drug Discovery
Associate Prof. Jing An
Bioassay & Screening
Prof. Debashis Ghosh
Structure Determination,
Assistant Prof. Juntao Luo
Drug Delivery,
Associate Prof. Ying Huang
Target Discovery
Assistant Prof. Golam Mohi
Preclinical Development

3-12-03 vMIP-II
100 T20(HX/X4)
D10(HX/X4)
Prof. Ziwei Huang
Comparison of a new
CXCR4 inhibitor, RCP168 with T20 Peptide, an anti-
HIV drug (J. Virol., 2007) D10-vMIP-II
80
60
40
20
0
-500 0 500 1000 1500 2000
Harvard Medical School
2500 3000
[Peptide] (nM)
Data from Prof. Joseph Sodroski,
3500
Prof. Debashis Ghosh
First crystal structure of aromatase and its complex with breast cancer drug (Nature,
2009)

Prof. Jing An
Combinational therapy with a novel Bcl-2 inhibitor HA14-1 and low doses of gamma radiation
(Oncogene, 2007)
1
1
0.1
0.01
0 0.25 0.5 0.75 1
Radiation dose (Gy)
H0/HL60/neo
H10/HL60/neo
H0/HL60/Bcl-2
H10/HL60/Bcl-2
0.1
0.01
0
H0/LNCaP
H10/LNCaP
H0/LNCaP/Bcl-2
H10/LNCaP/Bcl-2
Expon.
(H0/LNCaP/Bcl-2)
2 4
Radiation Dose (Gy)
6
Prof. Juntao Luo
Novel nanocarrier for cancer imaging and cancer treatment
(Bioconjugate Chem.,
2010)
Telodendrimer
HO
HO
HO
HO
HO
CH
HO
CH
3
CH
3
O
NH
O
NH
O
CH
3
OH
OH
O
112
H
N
O
N
H n
H
3
C H
3
C
N
3
H
N
O
O
O H
N
HN O
O
H
N
O
NH
O
N
H
H
3
C
OH
OH
For Ligand conjugation
Boc
NH
For conjugation
Of drug and probe molecules
O
NH
O
NH
N
H
O
H
N
O
HN
O
H
3
C
H
3
C
OH
H
3
C
O
NH
H
3
C
H
3
C
N
H
O
OH
H
3
C
H
3
C
OH
OH
OH
OH
OH
H
3
C
OH
H
3
C
OH
Selfassemble
OH
Theranostic
Micelle
PEG
Radio nuclide, drug or fluorescence probe
Tumor
Targeting
EPR
Paclitaxel &
Fluorescence dye,
QD or SPIO
Imaging & treatment

Translating the Research Power of
Upstate/Central New York to
Clinical and Industrial Applications
SUNY Upstate
Cancer Research Institute
New York City

Successful translation of a novel CD4 inhibitor to human clinical trials and commercialization
•
CD4 inhibitor currently in a
Phase II human clinical trial in cancer patients who have bone marrow transplantation for the prevention of Graft-Versus Host
Disease (GVHD)
• Promising new therapy for patients with cancer, immune disorders or transplant rejection

Upstate Cancer Research Institute (CRI) www.upstate.edu/CRI/
Department of Pharmacology www.upstate.edu/pharm